Several works have endorsed a significant role of the immune system and inflammation in the pathogenesis of heart failure. As indirect evidence, an association between a low relative lymphocyte count (RLC%) and worse outcomes found in this population has been suggested. Nevertheless, the role of RLC% for risk stratification in a large and nonselected population of patients with acute heart failure (AHF) has not yet been determined. Thus, the aim of this study was to determine the association between low RLC% and 1-year mortality in patients with AHF and consequently to define whether it has any role for early risk stratification. A total of 1,192 consecutive patients admitted for AHF were analyzed. Total white blood cell and differential counts were measured on admission. RLC% (calculated as absolute lymphocyte count/total white blood cell count) was categorized in quintiles and its association with all-cause mortality at 1 year assessed using Cox regression. At 1 year, 286 deaths (24%) were identified. A negative trend was observed between 1-year mortality rates and quintiles of RLC%: 31.5%, 27.2%, 23.1%, 23%, and 15.5% in quintiles 1 to 5, respectively (p for trend <0.001). After thorough covariate adjustment, only patients in the lowest quintile (<9.7%) showed an increased risk for mortality (hazard ratio 1.76, 95% confidence interval 1.17 to 2.65, p = 0.006). When RLC% was modeled with restricted cubic splines, a stepped increase in risk was observed patients in quintile 1: those with RLC% values <7.5% and <5% showed 1.95- and 2.66-fold increased risk for death compared to those in the top quintile. In conclusion, in patients with AHF, RLC% is a simple, widely available, and inexpensive biomarker, with potential for identifying patients at increased risk for 1-year mortality.
Current evidence supports a pathogenic role of the immune system and inflammation in the pathogenesis of heart failure (HF). A low relative lymphocyte count (RLC%) has been related to worse outcomes in selected patients with HF. In the present study, we sought to determine the association between low RLC% assessed on admission and 1-year all-cause mortality in patients consecutively admitted with diagnoses of acute HF (AHF).
Methods
We prospectively studied a cohort of 1,268 patients, consecutively admitted to the cardiology department at Hospital Clínico Universitario de Valencia from January 1, 2004, to July 1, 2009, with diagnoses of AHF. AHF was defined as the rapid onset of symptoms and signs secondary to abnormal cardiac function and the presence of objective evidence of structural or functional abnormalities of the heart at rest (such as cardiomegaly, third heart sound, cardiac murmur, abnormality on echocardiography, or increased natriuretic peptides). Patients with clinical evidence of cancer (n = 18), hematologic disturbances (n = 12), chronic inflammatory disease (n = 11), pneumonia (n = 16), sepsis (n = 8), and treatment with corticosteroids (n = 11) were excluded, leaving a final study sample of 1,192 patients.
Total white blood cell (WBC), neutrophil, lymphocyte, and monocyte counts were obtained on admission, using an automated blood cell counter. RLC% was calculated as the ratio between lymphocyte count and total WBC count. Follow-up was limited to 1 year, and patients were censored if they died, underwent cardiac valve replacement, or underwent cardiac transplantation within this period. All-cause mortality and cardiovascular (CV) mortality were chosen as the main and secondary end points, respectively. Survival status was ascertained either during the patient’s hospitalization, by phone contact with the patient or family members, or by routine clinic visits. Information about the cause of death was extracted from the patient’s clinical chart, adjudicated by an investigator who was blinded to lymphocyte values, and further categorized according to the American Heart Association classification. Deaths were considered not CV in origin if a specific non-CV cause was identified. Otherwise, CV origin was considered and included sudden death, progressive HF death, deaths attributable to other CV causes (such as myocardial infarction, stroke, etc.), and unknown causes of death. For the present study, those patients who died out of hospital (n = 39) were assumed to have died of CV causes. This study was approved by an institutional review committee, and all patients provided written informed consent.
Baseline characteristics were compared among quintiles of RLC% distribution. For continuous, normally distributed variables, comparisons were calculated using analysis of variance; for highly skewed variables, the Kruskal-Wallis rank test was used. The chi-square test was used for the comparison of discrete variables. Cumulative mortality curves and their differences were estimated with appropriate methods: Kaplan-Meier and Peto-Peto Prentice tests for total mortality and cumulative incidence function and Gray tests for CV mortality.
The independent effects of RLC% quintiles on long-term mortality and CV mortality were assessed by using Cox regression and Cox regression suited for competing risk events.
All variables listed in Table 1 were tested with prognostic purposes. Candidate covariates for multivariate analyses were chosen on the basis of previous medical knowledge, independent of their p values. Backward stepwise selection that kept the nominal type I error at 0.05 was used. During selection, the functional form of continuous variables was modeled by restricted cubic splines. The covariates included in the final models are listed at the bottom of Table 2 . For the 2 end points, the proportionality assumption was tested. Model discrimination was assessed using Harrell’s C-statistic. Cox model calibration was tested using the Gronnesby and Borgan test. The increment in the prognostic utility of adding lymphocyte count to the clinical model was determined using the integrated discrimination improvement index. Two-sided p values <0.05 were considered statistically significant for all analyses. All analyses were performed using Stata version 11.1 (StataCorp LP, College Station, Texas).
| Variable | Q1 (1.5%–9.7%) | Q2 (9.7%–14%) | Q3 (14.1%–18.4%) | Q4 (18.4%–24.6%) | Q5 (24.7%–62.7%) | p Value for Trend |
|---|---|---|---|---|---|---|
| (n = 239) | (n = 238) | (n = 239) | (n = 238) | (n = 238) | ||
| Age (years) | 75 ± 9 | 74 ± 11 | 73 ± 12 | 72 ± 12 | 71 ± 12 | 0.001 |
| Women | 125 (52.5%) | 119 (49.8%) | 125 (52.5%) | 119 (49.8%) | 118 (49.6%) | 0.566 |
| Previous admission for AHF | 107 (45%) | 88 (36.8%) | 96 (40.3%) | 84 (35.1%) | 70 (29.4%) | 0.001 |
| Hypertension | 191 (80.2%) | 184 (77%) | 182 (76.5%) | 176 (73.6%) | 188 (79%) | 0.494 |
| Dyslipidemia | 99 (41.6%) | 104 (43.5%) | 100 (42%) | 99 (41.4%) | 112 (47.1%) | 0.385 |
| Current smoker | 24 (10.1%) | 21 (8.8%) | 24 (10.1%) | 27 (11.3%) | 28 (11.8%) | 0.348 |
| Previous smoker | 42 (17.6%) | 58 (24.3%) | 45 (18.9%) | 38 (15.9%) | 40 (16.8) | 0.208 |
| Ischemic heart disease | 99 (41.6%) | 91 (38.1%) | 70 (29.4%) | 87 (36.4%) | 108 (45.4%) | 0.555 |
| Valvular heart disease | 70 (29.4%) | 64 (26.8%) | 77 (32.3%) | 73 (30.5%) | 56 (23.5%) | 0.389 |
| Acute decompensated HF | 163 (68.5%) | 173 (72.4%) | 176 (73.9%) | 181 (75.7%) | 127 (53.4%) | 0.005 |
| Acute pulmonary edema | 59 (24.8%) | 46 (19.2%) | 35 (14.7%) | 38 (15.9%) | 77 (32.3%) | 0.162 |
| Chronic pulmonary obstructive disease | 55 (23.1%) | 58 (24.3%) | 50 (21%) | 44 (18.4%) | 43 (18.1%) | 0.056 |
| Stroke | 28 (11.8%) | 31 (13%) | 21 (8.8%) | 20 (8.4%) | 18 (7.6%) | 0.034 |
| Peripheral artery disease | 16 (6.7%) | 16 (6.7%) | 16 (6.7%) | 10 (4.2%) | 23 (9.7%) | 0.515 |
| Radiologic pleural effusion | 110 (46.2%) | 122 (51%) | 115 (48.3%) | 103 (43.1%) | 78 (32.8%) | 0.001 |
| Peripheral edema | 139 (58.4%) | 139 (58.2%) | 149 (62.6%) | 134 (56.1%) | 106 (44.5%) | 0.003 |
| Previous use of diuretics | 165 (68.3%) | 149 (62.3%) | 156 (65.5%) | 140 (58.6%) | 131 (55%) | 0.001 |
| Previous use of β blockers | 45 (18.9%) | 57 (23.8%) | 63 (26.5%) | 67 (28%) | 56 (23.5%) | 0.126 |
| Previous use of angiotensin converting enzyme inhibitors/angiotensin II receptor blockers | 109 (45.8%) | 115 (48.1%) | 112 (47.1%) | 105 (43.9%) | 101 (42.4%) | 0.285 |
| Previous use of statins | 56 (23.5%) | 61 (25.5%) | 65 (27.3%) | 69 (28.9%) | 72 (30.2%) | 0.065 |
| Heart rate (beats/min) | 99 ± 27 | 100 ± 27 | 101 ± 31 | 100 ± 30 | 107 ± 31 | 0.072 |
| Systolic blood pressure (mm Hg) | 144 ± 34 | 148 ± 34 | 149 ± 36 | 145 ± 34 | 162 ± 38 | <0.001 |
| Diastolic blood pressure (mm Hg) | 78 ± 18 | 81 ± 18 | 83 ± 22 | 81 ± 20 | 89 ± 21 | <0.001 |
| Atrial fibrillation | 106 (44.5%) | 111 (46.4%) | 115 (48.3%) | 108 (45.2%) | 90 (37.8%) | 0.149 |
| QRS interval >120 ms | 65 (27.3%) | 66 (27.6%) | 60 (25.2%) | 63 (26.4%) | 77 (32.3%) | 0.337 |
| Hemoglobin (g/dl) | 12.4 ± 1.8 | 12.5 ± 1.8 | 12.7 ± 1.8 | 12.6 ± 1.7 | 13.2 ± 2 | <0.001 |
| Serum creatinine (mg/dl) | 1.43 ± 0.68 | 1.34 ± 0.68 | 1.25 ± 0.45 | 1.26 ± 0.49 | 1.26 ± 0.48 | 0.053 |
| Uric acid (mg/dl) | 7.9 ± 2.6 | 8.1 ± 2.6 | 7.8 ± 2.4 | 8 ± 2.4 | 7.7 ± 2.1 | 0.503 |
| Sodium (mEq/L) | 137 ± 5 | 139 ± 5 | 139 ± 5 | 140 ± 4 | 139 ± 4 | <0.001 |
| Troponin I ⁎ (ng/ml) | 0 (0.43) | 0 (0.32) | 0 (0.22) | 0 (0.22) | 0 (0.40) | 0.275 |
| Troponin I >0.2 ng/ml | 81 (34%) | 68 (28.4%) | 65 (27.3%) | 62 (25.9%) | 77 (32.3%) | 0.530 |
| Brain natriuretic peptide ⁎ (pg/ml) | 254 (328) | 266 (328) | 285 (339) | 270 (370) | 257 (370) | 0.931 |
| Antigen carbohydrate 125 ⁎ (U/ml) | 58.3 (109.4) | 81.8 (128.2) | 65.3 (110.5) | 75.8 (115) | 42.6 (94.6) | 0.122 |
| Echocardiography | ||||||
| Left ventricular ejection fraction ≤50% | 107 (45%) | 101 (42.3%) | 115 (48.3%) | 128 (53.6%) | 124 (52.1%) | 0.012 |
| Left atrial diameter (mm) | 43 ± 8 | 44 ± 8 | 45 ± 9 | 44 ± 7 | 43 ± 7 | 0.986 |
| Left ventricular diastolic diameter (mm) | 54 ± 9 | 54 ± 9 | 56 ± 9 | 57 ± 10 | 57 ± 9 | <0.001 |
| Septum (mm) | 11.6 ± 2.2 | 11.5 ± 2.4 | 11.6 ± 2.8 | 11.2 ± 2.2 | 11.3 ± 2.4 | 0.175 |
| Posterior wall (mm) | 11.3 ± 1.8 | 11.2 ± 2.2 | 11.4 ± 2.2 | 11.2 ± 1.9 | 11.3 ± 2.1 | 0.768 |
| Medications | ||||||
| β blockers | 110 (46.2%) | 113 (47.3%) | 128 (53.8%) | 140 (58.6%) | 103 (54.6%) | 0.006 |
| Diuretics | 235 (98.7%) | 233 (97.5%) | 234 (98.3%) | 235 (98.3%) | 233 (97.9%) | 0.761 |
| Spironolactone | 43 (18.1%) | 41 (17.1%) | 39 (16.4%) | 50 (20.9%) | 49 (20.6%) | 0.269 |
| Angiotensin converting enzyme inhibitors | 108 (45.4%) | 97 (40.6%) | 105 (44.1%) | 91 (38.1%) | 113 (47.5%) | 0.869 |
| Angiotensin II receptor blockers | 50 (21%) | 68 (28.4%) | 77 (32.3%) | 74 (31%) | 66 (27.7%) | 0.083 |
| Statins | 83 (34.9%) | 76 (31.8%) | 72 (30.2%) | 90 (37.7%) | 100 (42%) | 0.040 |
| Oral anticoagulants | 98 (41.2%) | 108 (45.2%) | 96 (40.3%) | 99 (41.4%) | 79 (33.2%) | 0.050 |
| Nitrates | 58 (24.4%) | 53 (22.2%) | 33 (13.9%) | 45 (18.8%) | 49 (20.6%) | 0.183 |
| Digoxin | 68 (28.6%) | 59 (24.7%) | 66 (27.7%) | 61 (25.5%) | 48 (20.2%) | 0.074 |
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